Recent genome-wide association scans have resulted in the identification of a large number of genes which are associated with autoimmunity. Identifying the functional outcome of these genetic variants is an important step in understanding the underlying mechanisms of these diseases. Several genetic variants have been linked to multiple diseases, indicating that common mechanisms are at play in these diseases. One such genetic variant is the PTPN22 1858T. This variant is associated with T1D, RA, Graves Disease, myasthenia gravis and SLE. This variant leads to a single amino acid change in the phosphatase Lyp R620W, resulting in a dominant gain of function. We and others have demonstrated that this variant results in a blunted response to activation via the T cell receptor which suggests a mechanism by which this variant may enhance an individual's predisposition to autoimmunity. In this grant we propose to address the hypothesis that the impaired TCR signaling that results from the PTPN22 1858T variant shapes the immune response in a manner which favors the development of strong proinflammatory responses which favors the development of autoimmunity. We have focused these studies on those which can be performed with human subjects as the molecular interaction altered by this single amino acid change may be unique to human cells. We will address the impact that the Lyp R620W variant has on the differentiation, lineage commitment, proliferation and survival of human CD4 T cells in vitro and establish the underlying cellular and molecular mechanisms by which this variant alters the immune response. We will then address the global impact of this variant on the immune response in vivo by comparing the response to vaccination with pneumococcal vaccine conjugated to the carrier protein CRM197 in individuals who carry the disease associated variant to those of similarly matched subjects who do not. This will be done first with healthy subjects, followed by studies of individuals with T1D. We propose to do this in three specific aims: Aim 1) We will investigate the impact of impaired TCR signaling associated with the PTPN22 1858T allele on the commitment of naove T cells and the function and survival of memory T cells in vitro. Aim 2) We will test the hypothesis that individuals who possess the PTPN22 1858T allele develop an enhanced proinflammatory memory T cell response in vivo, following immunization with the polyvalent pneumococcal vaccine conjugated to the CRM197 carrier protein. Aim 3) We will examine how phenotypes associated with the LypR620W variant are expressed in the context of autoimmune diabetes. In T1D subjects where multiple genetic variants with potential immune impact are present, we will address T cell function with respect to PTPN22 1858T genotype both in vivo, and in vitro. PUBLIC HEALTH RELEVANCE: Project Narrative It is clear that genes play an important role in the development of autoimmune diseases;thus it is vital that we understand in what way a specific gene linked to autoimmunity influences the immune system. In this grant we will study the impact of the PTPN22 1858T gene on the immune response. This gene is associated with multiple autoimmune diseases;understanding the impact of this gene on the human immune system in both health and disease will help us understand the pathways which lead to autoimmunity.